NANOKRISTAL TEKNOLOJISI: ÇÖZÜNÜRLÜĞÜ DÜŞÜK İLAÇLARIN ORAL BIYOYARARLANIMIN ARTIRILMASI

Abstract

Nanokristal teknolojisi partikül boyutu 1000 nanometre (nm)’nin altında, herhangi bir taşıyıcı sisteme ihtiyaç duymadan katı ilaç partikülerinin üretilmesini sağlar. Sudaki çözünürlüğü düşük ilaçların partiküllerinin boyutunun küçültülmesi ile, yüzey alanlarının artması ve difüzyon tabakasının kalınlığının azaltılması k çözünürlük hızının da artışına yol açar. Buna bağlı olarak, absorpsiyon bölgesinde artan konsantrasyon gradienti bağırsak lümeni ve kan arasındaki pasif difüzyon yoluyla permeasyonu ve emilimi teşvik etmektedir. Dolayısıyla Biyofarmasötik Sınıflandırma Sistemi (BCS) Sınıf II ve IV’e ait ilaç molekülleri için nanokristal teknolojisi yaklaşımını kullanarak biyoyararlanımlarını geliştirmek ve/veya arttırmak oldukça önemlidir. Nanometre boyutunda ilaç partikülü elde edebilmek için yukarıdan aşağıya (top-down) ve aşağıdan yukarıya (bottom-up) yöntemlerinden yararlanılmaktadır. İlaç endüstrisinde uygulama kolaylığı, tekrar edilebilirliği ve ölçeklendirilebilmesi nedeniyle bilyeli değirmende yaş öğütme (BWM) ve yüksek basınçlı homojenizasyon (HPH) olarak alt bölümlere ayrılan yukarıdan aşağıya yöntemleri tercih edilmektedir. Nanokristal teknolojisi ile ilaç endüstrisinde hâlihazırda tedavide onaylanmış olan ilaç moleküllerinin daha az yan etki, daha düşük dozlar ve daha hızlı etki başlangıcı sağlayarak yeni dozaj formlarının geliştirilmesi ve yeni ilaç moleküllerinin daha iyi bir biyoyararlanımla formüle edilebilmesi amaçlanmaktadır.

Keywords

• Nanokristal teknolojisi
• suda çözünür ilaçlar
• oral yol
• hazırlama yöntemleri

NANOCRYSTAL TECHNOLOGY: INCREASING ORAL BIOAVAILABILITY OF LOW-SOLUBLE DRUGS

Abstract

Nanocrystal technology enables the production of solid drug particles with a particle size below 1000 nm without the need for any carrier system. By reducing the size of the particles of drugs with low solubility in water, increasing the surface area and decreasing the thickness of the diffusion layer leads to an increase in k the solubility rate. Accordingly, the increasing concentration gradient in the absorption zone promotes permeation and absorption by passive diffusion between the intestinal lumen and blood. Therefore, it is very important to improve and / or increase their bioavailability by using the nanocrystal technology approach for drug molecules belonging to BCS Class II and IV. Top-down and bottom-up methods are used to obtain nanometer-sized drug particles. In the pharmaceutical industry, top-down methods, which are subdivided into wet milling (BWM) and high pressure homogenization (HPH), are preferred in the ball mill because of its ease of application, repeatability and scalability. With nanocrystal technology, it is aimed to create new dosage forms by providing less side effects, lower doses and faster onset of action of drug molecules that are already approved in the pharmaceutical industry. It is also aimed that new drug molecules can be formulated with better bioavailability.

Keywords

• Nanocrystal technology
• Water-soluble drugs
• Oral route
• Methods of preparation

References

1. 1. Kalepu S, Nekkanti V. Insoluble drug delivery strategies : review of recent advances and business prospects. Acta Pharm Sin B 2015;5(5):442-53.
2. 2. Augustijns P, Wuyts B, Hens B, Annaert P, Butler J, Brouwers J. A review of drug solubility in human intestinal fluids : Implications for the prediction of oral absorption. Eur J Pharm Sci 2014;57:322-32.
3. 3. Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins : basic science and product development. J Pharm Pharmacol 2010;62:1607-21.
4. 4. Kawabata Y, Wada K, Nakatani M, Yamada S, Onoue S. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system : Basic approaches and practical applications. Int J Pharm 2011;420:1- 10.
5. 5. Wu C, Benet LZ. Predicting Drug Disposition via Application of BCS : Transport / Absorption / Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System Pharm Res 2005;22(1):11- 23.
6. 6. Butler JM, Dressman JB. The Developability Classification System : Application of Biopharmaceutics Concepts to Formulation Development. J Pharm Sci 2010;99(12):4940-54.
7. 7. Möschwitzer JP. Drug nanocrystals in the commercial pharmaceutical development process. Int J Pharm 2012;453:142-56.
8. 8. Merisko-liversidge E, Liversidge GG, Cooper ER. Nanosizing : a formulation approach for poorly-water-soluble compounds. Eur J Pharm Sci 2003;18:113-20.

9. 9. Hou Y, Shao J, Fu Q, Li J, Sun J, He Z. Spray-dried nanocrystals for a highly hydrophobic drug : Increased drug loading, enhanced redispersity, and improved oral bioavailability. Int J Pharm 2017;516(1-2):372-9.
10. 10. Cheng M, Yuan F, Liu J, Liu W, Feng J, Jin Y, Tu L. Fabrication of Fine Puerarin Nanocrystals by Box – Behnken Design to Enhance Intestinal Absorption. AAPS PharmSciTech 2020:1-12.
11. 11. Soisuwan S, Teeranachaideekul V, Wongrakpanich A. Impact of uncharged and charged stabilizers on in vitro drug performances of clarithromycin nanocrystals. Eur J Pharm Biopharm 2019;137:68-76.
12. 12. Seto Y, Ueno K, Suzuki H, Sato H, Onoue S. Development of novel lutein nanocrystal formulation with improved oral bioavailability and ocular distribution. J Funct Foods 2019;61:103499.
13. 13. Shah DA, Murdande SB, Dave RH. A Review : Pharmaceutical and Pharmacokinetic Aspect of Nanocrystalline Suspensions. J Pharm Sci 2016;105:10-24.
14. 14. Ren X, Qi J, Wu W, Yin Z, Li T, Lu Y. Development of carrier-free nanocrystals of poorly watersoluble drugs by exploring metastable zone. Acta Pharmacol Sinic 2019;9(1):118-27.
15. 15. Chen L, Wang Y, Zhang J, Hao L, Guo H, Lou H, Zhang D. Bexarotene nanocrystal — Oral and parenteral formulation development, characterization and pharmacokinetic evaluation. Eur J Pharm Biopharm 2014;87(1):160-9.
16. 16. Ferrar JA, Sellers BD, Chan C, Leung DH. Towards an improved understanding of drug excipient interactions to enable rapid optimization of nanosuspension formulations. Int J Pharm 2020;578:119094.
17. 17. Bitterlich A, Laabs C, Krautstrunk I, Dengler M, Juhnke M, Grandeury A, Bunyes H, Kwade A. Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling. Eur J Pharm Biopharm 2015;92:171-9.
18. 18. Peltonen L, Hirvonen J. Drug nanocrystals – Versatile option for formulation of poorly soluble materials. Int J Pharm 2018;537(1-2):73- 83.
19. 19. Sarnes A, Kovalainen M, Häkkinen MR, Laaksonen T, Laru J, Kiessevara J, Ilkka J, Oksala O et al. Nanocrystal-based per-oral itraconazole delivery : Superior in vitro dissolution enhancement versus Sporanox ® is not realized in in vivo drug absorption. J Control Release 2014;180:109-16.
20. 20. Buraphacheep V, Morakul B. Nanocrystals for enhancement of oral bioavailability of poorly water-soluble drugs. Asian J Pharm Sci 2015;10(1):13-23.
21. 21. He Y, Ye Z. Can machine learning predict drug nanocrystals? J Control Release 2020;322:274- 85.
22. 22. Eerdenbrugh B Van, Mooter G Van Den, Augustijns P. Top-down production of drug nanocrystals : Nanosuspension stabilization , miniaturization and transformation into solid products. Int J Pharm 2008;364:64-75.
23. 23. Shegokar R, Müller RH. Nanocrystals : Industrially feasible multifunctional formulation technology for poorly soluble actives. Int J Pharm 2010;399(1-2):129-39.
24. 24. Liu P, Rong X, Laru J, et al. Nanosuspensions of poorly soluble drugs : Preparation and development by wet milling. Int J Pharm 2011;411(1-2):215-22.
25. 25. Fontana F, Figueiredo P, Zhang P, Hirvonen JT, Liu D, Santos HA. Production of pure drug nanocrystals and nano co-crystals by con fi nement methods. Adv Drug Deliv Rev 2018;131:3-21.
26. 26. Gao L, Zhang D, Chen M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J Nanopart Res 2008;10:845-62.
27. 27. Keck CM, Mu RH. Drug nanocrystals of poorly soluble drugs produced by high pressure homogenisation. Eur J Pharm Biopharm 2006;62:3-16.
28. 28. Krause KP, Kayser O, Ma K, Gust R, Mu RH. Heavy metal contamination of nanosuspensions produced by high-pressure homogenisation. Int J Pharm 2000;196:169-72.
29. 29. Hui Z, Kumar A, Wan P, Heng S. ScienceDirect Overview of milling techniques for improving the solubility of poorly water-soluble drugs. Asian J Pharm Sci 2015;10(4): 255-74.
30. 30. Gora S, Mustafa G, Sahni JK, Ali J, Baboota S. Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension : pharmacokinetics and pharma- codyanamic study. Drug Deliv 2016;23(3):940-50.
31. 31. Li W, Quan P, Zhang Y, Cheng J, Liu J, Cun D. Influence of drug physicochemical properties on absorption of water insoluble drug nanosuspensions. Int J Pharm 2014;460:13-23.
32. 32. Dong Y, Kiong W, Hu J, Shen S, Tan RBH. A continuous and highly effective static mixing process for antisolvent precipitation of nanoparticles of poorly water-soluble drugs. Int J Pharm 2010;386:256-61.
33. 33. Hu J, Kiong W, Dong Y, Shen S, Tan RBH. Continuous and scalable process for waterredispersible nanoformulation of poorly aqueous soluble APIs by antisolvent precipitation and spray-drying. Int J Pharm 2011;404:198-204.
34. 34. Xia D, Quan P, Piao H, Sun S, Yin Y, Cui F. Preparation of stable nitrendipine nanosuspensions using the precipitation – ultrasonication method for enhancement of dissolution and oral bioavailability. Eur J Pharm Sci 2010;40:325-34.
35. 35. Liu J, Tu L. Mechanisms for oral absorption enhancement of drugs by nanocrystals. J Drug Deliv Sci Technol 2020;56:101607.
36. 36. Shair I, Hu H, Yin L, He W. Drug nanocrystals : Fabrication methods and promising therapeutic applications. Int J Pharm 2019;562:187-202.
37. 37. Sinha B, Müller RH, Möschwitzer JP. Bottomup approaches for preparing drug nanocrystals : Formulations and factors affecting particle size. Int J Pharm 2013;453:126-41.
38. 38. Kesisoglou F, Wu Y. Understanding the Effect of API Properties on Bioavailability Through Absorption Modeling. AAPS J 2008;10(4):516- 25.
39. 39. Ueda K, Iwai T, Sunazuka Y, Chen Z, Kato N, Higashi K. Effect of molecular weight of hypromellose on mucin diffusion and oral absorption behavior of fenofibrate nanocrystal. Int J Pharm 2019;564:39-47.
40. 40. Guo M, Wei M, Li W, Guo M, Guo C, Ma M, et al. Impacts of particle shapes on the oral delivery of drug nanocrystals : Mucus permeation , transepithelial transport and bioavailability. J Control Release 2019;307:64-75.
41. 41. Deng F, Zhang H, Wang X, Zhang Y, Hu H, Song S, et al. The transmembrane pathways and mechanisms of rod-like paclitaxel nanocrystals through MDCK polarized monolayer. Appl Mater Interfaces 2017;9(7):5803-16.
42. 42. Pawar VK, Singh Y, Meher JG, Gupta S, Chourasia MK. Engineered nanocrystal technology : Invivo fate , targeting and applications in drug delivery. J Control Release 2014;183:51-66.
43. 43. Fu Q, Sun J, Ai X, Zhang P, Li M, Wang Y, et al. Nimodipine nanocrystals for oral bioavailability improvement : Role of mesenteric lymph transport in the oral absorption. Int J Pharm 2013;448:290-7.
44. 44. Müller RH, Jacobs C. Buparvaquone mucoadhesive nanosuspension : preparation , optimisation and long-term stability. Int J Pharm 2002;237:151-61.
45. 45. Fu Q, Ma M, Li M, Wang G, Guo M, Li J, et al. Improvement of oral bioavailability for nisoldipine using nanocrystals. Powder Technol 2017;305(103):757-63.
46. 46. Lai F, Pini E, Angioni G, Manca ML, Perricci J, Sinico C, Fadda AM. Nanocrystals as tool to improve piroxicam dissolution rate in novel orally disintegrating tablets. Eur J Pharm Biopharm 2011;79:552-8.
47. 47. Junghanns JAH, Müller RH. Nanocrystal technology , drug delivery and clinical applications. Int J Nanomedicine 2008;3(3):295- 309.
48. 48. Chen M, John M, Lee SL, Tyner KM. Development Considerations for Nanocrystal Drug Products. AAPS J 2017;19(3):642-51.
49. 49. Basu A, Guti S, Kundu S, Das A, Das S, Mukherjee A. Oral andrographolide nanocrystals protect liver from paracetamol induced injury in mice. J Drug Deliv Sci Technol 2020;55:101406.
50. 50. Singare DS, Marella S, Gowthamrajan K, Kulkarni GT, Vooturi R, Srinivasa P. Optimization of formulation and process variable of nanosuspension : An industrial perspective. Int J Pharm 2010;402(1-2):213-20.